22 april 2022: Bron: BMC Cancer volume 20, Article number: 772 (2020)
Eerder al hebben we informatie over het Cubaanse CIMAvax-EGF vaccin bij niet-kleincellige longkanker gegeven in dit artikel. N.a.v. een vraag van een bezoeker onderaan dat artikel ben ik op zoek gegaan naar extra informatie en kwam daar paar interessante nieuwe studies tegen. Dit CIMAvax-EGF vaccin zou ook wel eens effectief kunnen zijn bij andere vormen van kanker met solide tumoren met een EGFR mutatie. De epidermale groeifactorreceptor (EGFR) is een signaaleiwit dat zich op de celmembraan bevindt. Wanneer de epidermale groeifactor (EGF) zich bindt aan deze receptor, dan leidt dit tot celgroei en celdeling.
CIMAvax-EGF bleek eerder al veilig en effectief te zijn bij de behandeling van patiënten met gevorderde niet-kleincellige longkanker (NSCLC) in verschillende klinische onderzoeken [zie referenties 1,2,3,4,5]. Er zijn echter aanwijzingen voor verschillende reacties op het vaccin. De ene patiént reageert wel goed, de andere patiënt helemaal niet. In deze studie [zie ref. 6] werden patiënten met korte- en langetermijnoverleving onderscheiden tussen degenen die werden behandeld met CIMAvax-EGF.
In verschillende fase II- en fase IIL studies die afgelopen jaren werden uitgevoerd, blijkt de patiënt die een "goede antilichaamrespons" (anti-EGF-antilichaamtiters ≥ 1:4000 seraverdunning) ontwikkelde een beduidend betere overleving te hebben in vergelijking met patiënten die een lagere anti-EGF-antilichaamrespons hadden. [zie referenties 1, 3, 4].
Aan de andere kant werd de correlatie tussen EGF-concentratie bij aanvang van de behandeling en uiteindelijke overlevingsduur waargenomen sinds de eerste fase I-studie [zie referentie 5]. De daaropvolgende studies bevestigden ook dit feit, gevaccineerde patiënten met een serum basale EGF-concentratie > 870 pg/ml vertoonden een betere mediane overleving in vergelijking met controles met hetzelfde EGF-serumniveau [1, 2].
Bovendien waren biomarkers die wijzen op veroudering van het immuunsysteem (immunosenescentie-biomarkers) als deel uitmakend van CD8 + CD28−-cellen, CD4-cellen en de CD4/CD8-ratio na eerstelijns chemotherapie ook geassocieerd met klinisch voordeel van het CIMAvax-EGF vaccin. Al deze onderzoeken wijzen op het belang dat wordt gehecht aan het zoeken naar voorspellende biomarkers die het mogelijk maken om patiënten te selecteren die echt voordeel kunnen halen uit het vaccin.
En die voorspellende biomarkers zijn nu gezamenlijk en apart onderzocht. Zo blijkt uit deze studie (abstract staat verderop in dit artikel) dat bepaalde bloedwaarden (perifere bloedparameters) en biomarkers die wijzen op veroudering van het immuunsysteem (immunosenescentie-biomarkers) samen met een basale EGF-concentratie in het bloed goede voorspellers van het wel of niet mogelijke aanslaan van het CIMAvax-EGF vaccin bij patiënten met gevorderde niet-kleincellige longkanker.
Zo werden de gegevens van patiënten uit een gecontroleerde klinische studie retrospectief geanalyseerd om te kijken welke biomarkers voor het effect van het CIMAvax-EGF vaccin voorspellende waarde hadden.
Mogelijke voorspellende biomarkers voor de behandeling die werden onderzocht waren basale serum EGF-concentratie, perifere bloedparameters en immunosenescentie-biomarkers. Met daarbij het aandeel dat CD8 + CD28- T-cellen, CD4+ en CD8+ T-cellen, CD4/CD8-verhouding en CD19+ B-cellen daarin hadden.
In de analyse werden ook de 33 patiënten die goed reageerden op het CIMAvax-EGF vaccin meegenomen in de analyse, maar dus ook de patiënten die minder goed reageerden of helemaal niet reageerden. Voor alle mogelijke modellen is de voorspellende causale informatie (PCI) berekend. Het model met een minimaal aantal voorspellers, maar met een hoge voorspellingsnauwkeurigheid (PCI > 0.7) werd geselecteerd.
Uit de analyse bleek dat het gemiddelde van de voorspellende causale informatie (PCI) steeg van 0,486, wanneer slechts één voorspeller werd bekeken, tot 0,98 bij gebruik van de multivariate benadering met alle voorspellers.
Het model dat het aantal CD4+ T-cellen, basale epidermale groeifactor (EGF)-concentratie, neutrofiel tot lymfocytverhouding, monocyten en neutrofielen als voorspellers beschouwt, werd geselecteerd (PCI > 0.74).
Patiënten die volgens de biomarkerwaarden vóór de behandeling werden voorspeld als goede responders die met CIMAvax-EGF werden behandeld, hadden een significant hogere waargenomen overleving vergeleken met de controlegroep (p = 0,03). Er werd geen verschil waargenomen voor slechte responders tussen de prognose en het uiteindelijke resultaat.
Predictive probability of treatment success for three examples of a Good responder (basal EGF concentration = 1700, CD4+ T cells = 65, CD4/CD8 ratio = 3, NLR = 2, Neutrophils = 50), b Rare (basal EGF concentration = 900, CD4+ T cells =35, CD4/CD8 ratio = 3, NLR = 2, Neutrophils = 55) and c Bad responders (basal EGF concentration = 200, CD4+ T cells =10, CD4/CD8 ratio = 1, NLR = 1, Neutrophils = 60) to CIMAvax-EGF
Kaplan Meier survival curves for patient treated with CIMAvax-EGF and control for a) good responders, b) bad responders
Klein stukje nog uit Wikipedia over CIMAvax-EGF vaccin met daarin verwijzingen naar studies die al gedaan zijn en nog lopende studies, ook in Europa verkrijgbaar:
CimaVax-EGF is a vaccine used to treat cancer, specifically non-small-cell lung carcinoma (NSCLC). CIMAvax-EGF is composed of recombinant human epidermal growth factor (EGF) conjugated to a protein carrier.[1]
The vaccine was developed by the Center of Molecular Immunology, Havana, Cuba.[2][3] There are agreements in place to test it in the United States, Japan, and some European countries.[4] It is currently available in Cuba, Colombia, Bosnia and Herzegovina, Peru and Paraguay.[5] In October 2015 Serbia's Institute of Virology, Vaccines and Sera (AKA Torlak Institute) signed a memorandum for use in 30 patients as part of a study.[6] CimaVax is relatively cheap to produce and store, and has low toxicity.[4] Side effects of the vaccine appear to be mild, and include chills, fever, and feeling sick.[7][8]>>>>>>lees verder
Hier de twee abstracten van bovengenoemde studies met bijbehorende referenties. In deze eerste studie ook verwijzingen naar CIMAvax-EGF gegeven in combinatie met anti-PD medicijnen, met ook studies bij andere vormen van kanker waaronder darmkanker, alvleesklierkanker enz. maar lees het hele studierapport want is teveel om dat hier apart te noemen. Klik op de titel van het abstract:
ABSTRACT
We previously reported that CIMAvax-EGF vaccine is safe, immunogenic and efficacious to treat advanced non-small-cell lung cancer (NSCLC) patients. A phase III trial was designed using an optimized immunization schedule. It included higher antigen dose and injections at multiple sites. Immune response and circulating biomarkers were studied in a subset of patients. EGF-specific antibody titers, IgG subclasses, peptide immunodominance and circulating biomarkers were assessed by ELISA. In vitro EGF-neutralization capacity of immune sera and EGF-IgG binding kinetics was evaluated by Western Blot and Surface Plasmon Resonance (SPR) technology, respectively. We show that CIMAvax-EGF elicited mainly IgG3/IgG4 antibodies at titers exceeding 1:4000 in 80% of vaccinated patients after 3 months of treatment. The EGF-specific humoral response was directed against the central region of the EGF molecule. For the first time, the kinetic constants of EGF-specific antibodies were measured evidencing affinity maturation of antibody repertoire up to month 12 of vaccination. Notably, the capacity of post-immune sera to inhibit EGFR phosphorylation significantly increased during the course of the immunization scheme and was related to clinical outcome (P = .013, log-rank test). Basal concentrations of EGF and TGFα in the serum were affected by EGF-based immunization. In conclusion, the CIMAvax-EGF vaccine induces an EGF-specific protective humoral response in a high percent of NSCLC vaccinated patients, the quantity and quality of which were associated with clinical benefit (clinical trial registration number: RPCEC00000161, http://registroclinico.sld.cu/).
- Research article
- Open Access
- Published:
Identifying predictive biomarkers of CIMAvaxEGF success in non–small cell lung cancer patients
BMC Cancer volume 20, Article number: 772 (2020)
Abstract
Background
Immunosenescence biomarkers and peripheral blood parameters are evaluated separately as possible predictive markers of immunotherapy. Here, we illustrate the use of a causal inference model to identify predictive biomarkers of CIMAvaxEGF success in the treatment of Non–Small Cell Lung Cancer Patients.
Methods
Data from a controlled clinical trial evaluating the effect of CIMAvax-EGF were analyzed retrospectively, following a causal inference approach. Pre-treatment potential predictive biomarkers included basal serum EGF concentration, peripheral blood parameters and immunosenescence biomarkers. The proportion of CD8 + CD28- T cells, CD4+ and CD8+ T cells, CD4/CD8 ratio and CD19+ B cells. The 33 patients with complete information were included. The predictive causal information (PCI) was calculated for all possible models. The model with a minimum number of predictors, but with high prediction accuracy (PCI > 0.7) was selected. Good, rare and poor responder patients were identified using the predictive probability of treatment success.
Results
The mean of PCI increased from 0.486, when only one predictor is considered, to 0.98 using the multivariate approach with all predictors. The model considering the proportion of CD4+ T cell, basal Epidermal Growth Factor (EGF) concentration, neutrophil to lymphocyte ratio, Monocytes, and Neutrophils as predictors were selected (PCI > 0.74). Patients predicted as good responders according to the pre-treatment biomarkers values treated with CIMAvax-EGF had a significant higher observed survival compared with the control group (p = 0.03). No difference was observed for bad responders.
Conclusions
Peripheral blood parameters and immunosenescence biomarkers together with basal EGF concentration in serum resulted in good predictors of the CIMAvax-EGF success in advanced NSCLC. Future research should explore molecular and genetic profile as biomarkers for CIMAvax-EGF and it combination with immune-checkpoint inhibitors. The study illustrates the application of a new methodology, based on causal inference, to evaluate multivariate pre-treatment predictors. The multivariate approach allows realistic predictions of the clinical benefit of patients and should be introduced in daily clinical practice.
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Acknowledgements
We thank all participating patients and their families, as well as staffs of all the institutions involved in this study.
Funding
This study is part of the research activities of the Cuban-Flemish Training and Research Program in Data Science and Big Data Analysis, supported by Flemish Interuniversity Council (VLIR).
Author information
Affiliations
Contributions
PL, LS and AL conceived the study, WVE, AA and GM developed the methodology. PL, LS WVE, AA and GM Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis). AL, DS and TC participate in the clinical interpretation of the data. All authors critically revised subsequent drafts of the manuscript and approved the final version.
Corresponding authors
Ethics declarations
Ethics approval and consent to participate
The trial protocol, informed consent, investigator brochure, and case report forms were approved by the ethic boards from each participating institution, including the main investigation site: Hermanos Ameijeiras Hospital and by the Cuban Regulatory Agency (CECMED). Informed consent was obtained from each subject before entering in the study. The trial was conducted in accordance with the principles of the declaration of Helsinki and Good Clinical Practice guidelines. It was registered at the Cuban Registry of Clinical Trials, a WHO-validated public registry http://www.who.int/ictrp/network/rpcec/en, trial number RPCEC00000161).
Consent for publication
This manuscript does not contain any details, images, or videos that might leed to identification of an individual patient.
Competing interests
The authors declare that there are no conflicts of interest.
Additional information
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